bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–09–28
sixty-nine papers selected by
Catalina Vasilescu, Helmholz Munich
  1. A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
  2. Strategic Targeting of Mitochondria: Bridging Biology and Therapy for Health Benefits.
  3. The First Heterozygous TWNK Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases.
  4. Mitochondria expel tainted DNA - spurring age-related inflammation.
  5. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  6. Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
  7. The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
  8. Mitochondrial Complex I and ROS control neuromuscular function through opposing pre- and postsynaptic mechanisms.
  9. MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.
  10. Genetic and Clinical Investigations of C12orf65 Gene Mutations in Three Chinese Pedigrees.
  11. Softer nuclei for whiter brown fat.
  12. Cross-Organ Mitochondrial Communication in Stress and Disease.
  13. Leigh Syndrome Due to the Variant c.1019T>C in COX15.
  14. Reply: "Leigh Syndrome Due to the Variant c.1019T>C in COX15".
  15. Macromolecular Crowding in Mitochondria.
  16. Mitochondrial medicine in fatty acid oxidation disorders: insights from genetic discoveries and patient cell models.
  17. Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.
  18. Sensing within: Mitochondrial inside-out signal transduction.
  19. Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.
  20. Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
  21. Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.
  22. Mitochondrial cardiomyopathy: a puzzle for the final diagnosis - CORRIGENDUM.
  23. Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.
  24. Purine nucleotides are competitive inhibitors of apo-GOT1.
  25. Human polynucleotide phosphorylase in mitochondrial RNA metabolism.
  26. Hepatic ketogenic insufficiency blunts exercise-induced energy expenditure and alters mitochondrial proteins in skeletal muscle.
  27. Mitochondria-specific photorelease of ceramide induces apoptosis.
  28. Deep Intronic SVA_E Insertion Identified as the Most Common Pathogenic Variant Associated With Canavan Disease: A Diagnostic Blind Spot.
  29. Effective Reduction in Nuclear DNA Contamination Allows Sensitive Mitochondrial DNA Methylation Determination by LC-MS/MS.
  30. Molecular Cell Biology of Apoptosis in Health and Disease.
  31. Mitochondrial Complex IV Deficiency Nuclear Type 11 Caused by a Novel Start-Lost Variant in the COX20 Gene.
  32. A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.
  33. Metabolic cardiomyopathies: untangling clinical heterogeneity with human stem-cell derived models.
  34. geneEX: An Integrated Phenotype-Driven Algorithm for Rapid Identification of Causative Variants in Monogenic Disorders.
  35. Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.
  36. Mitochondria transported by Kinesin-3 prevent localized calcium spiking to inhibit caspase-dependent specialized cell death.
  37. Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements.
  38. Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
  39. Huntington's disease treated for first time using gene therapy.
  40. Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.
  41. Bmal1 deletion alters mitochondrial microstructure and function in mouse cone photoreceptors.
  42. Fetal Anemia and Periventricular Hyperechogenicity/Halo as a Prenatal Indicator of CoQ10 Deficiency Associated With Biallelic Variant in COQ2 Gene.
  43. A sensory and motor neuropathy caused by a genetic variant of NAMPT.
  44. Clinical features of Leber's hereditary optic neuropathy carrying a rare m.13051G>A mtDNA mutation.
  45. The B-lymphoblastoid model in Barth syndrome.
  46. First Case in Lithuania of an Autosomal Recessive Mutation in the DNAJC30 Gene as a Cause of Leber's Hereditary Optic Neuropathy.
  47. Animal Models of Parkinson's Disease.
  48. Natural Mutation in Naked Mole-Rat UCP1 Refutes Importance of the Histidine Pair Motif for Proton Conductance and Thermogenesis.
  49. Mitochondrial cardiolipin remodeling facilitates efficient myoblast differentiation.
  50. Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
  51. Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
  52. Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.
  53. Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
  54. DJ-1/PARK7 in Parkinson's disease: mechanisms of pathogenesis and therapeutic potential.
  55. NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions.
  56. INF2-Related Charcot-Marie-Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights.
  57. Acetylation of the Mitochondrial Chaperone GRP75 Governs ER-Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance.
  58. Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.
  59. A consensus guide to preclinical indirect calorimetry experiments.
  60. Efficient Installation of Heterozygous Mutations in Human Pluripotent Stem Cells Using Prime Editing.
  61. Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
  62. Supercomplex Restructuring in Heart Mitochondria of COX7A1-Deficient Mice.
  63. Rates of Mitochondrial Metabolism of Glucose, Amino Acids, and Fatty Acids by the HEI-OC1 Inner Ear Cell Line.
  64. Independent serum metabolomics approaches identify disrupted glutamic acid and serine metabolism in Parkinson's disease patients.
  65. A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.
  66. Beyond Ornithine Metabolism in Gyrate Atrophy: Tissue-Specific Proteomic Insights into Neonatal and Adult OAT Deficiency.
  67. Artificial Intelligence in the Diagnosis of Pediatric Rare Diseases: From Real-World Data Toward a Personalized Medicine Approach.
  68. Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
  69. A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR.
  1. Biomolecules. 2025 Aug 26. pii: 1230. [Epub ahead of print]15(9):
    A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
    Alessia Nasca, Alessia Catania, Andrea Legati, Rossella Izzo, Carola D'onofrio, Teresa Ciavattini, Eleonora Lamantea, Costanza Lamperti, Daniele Ghezzi.
      Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range of clinical phenotypes, ranging from isolated optic atrophy to severe neurological conditions. DNM1L encodes DRP1 (dynamin-1-like protein), which is a key player in mitochondrial and peroxisomal fission. This study describes two twin sisters with a de novo heterozygous variant in DNM1L, due to possible paternal germline mosaicism identified through clinical exome sequencing. The two twins showed a variable clinical presentation, including paraparesis and optic neuropathy. Functional studies of patient-derived fibroblasts revealed altered mitochondrial and peroxisomal morphology, along with dysregulated DNM1L transcript levels, indicating the deleterious effect of the variant. These findings allowed us to reclassify the identified variant from a variant of uncertain significance to a likely pathogenic variant. Our report provides insight into the phenotypic spectrum of DNM1L-related disorders and highlights the need to combine genetic and functional analyses to accurately diagnose rare mitochondrial diseases.
    Keywords:  DNM1L; mitochondrial and peroxisomes fission; mitochondrial disorders; mitochondrial dynamics; variant reclassification
    DOI:  https://doi.org/10.3390/biom15091230
  2. Cell Biochem Biophys. 2025 Sep 27.
    Strategic Targeting of Mitochondria: Bridging Biology and Therapy for Health Benefits.
    Gino A Kurian, Srijan Jayaraman, Eren Rose Gino.
      
    Keywords:  Mitochondrial inner membrane targeting; Mitochondrial matrix and precision medicine; Mitochondrial outer membrane targeting; Mitochondrial transport; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s12013-025-01915-y
  3. Biomolecules. 2025 Sep 18. pii: 1337. [Epub ahead of print]15(9):
    The First Heterozygous TWNK Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases.
    Diego Lopergolo, Gianna Berti, Gian Nicola Gallus, Silvia Bianchi, Filippo Maria Santorelli, Alessandro Malandrini, Nicola De Stefano.
       BACKGROUND: The TWNK gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. TWNK mutations are associated with a wide spectrum of clinical phenotypes and a marked heterogeneity. However, heterozygous nonsense variants in the gene have never been described in association with disease.
    METHODS: We analyzed a next-generation sequencing (NGS) targeted gene panel in a cohort including 40 patients with high clinical suspicion of mitochondrial disorders. Selected patients underwent a complete neurological examination, electrophysiology tests, and muscle biopsy. Segregation analysis was performed in available family members. The 3D structure of twinkle was visualized and analyzed using Swiss Model and Pymol version 3.1.6.1.
    RESULTS: We found four TWNK-mutated subjects from two unrelated families. They exhibited a variable clinical spectrum, ranging from asymptomatic individuals to subjects with psychiatric disorder, chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. All the subjects shared the heterozygous TWNK p.Glu665Ter variant.
    DISCUSSION AND CONCLUSIONS: We describe the clinical phenotype and muscle biopsy findings associated with the first reported heterozygous nonsense TWNK variant, thus expanding the current knowledge of Twinkle-related disorders. Our findings are in line with the high intrafamilial clinical variability associated with TWNK mutations. Although PEO and skeletal muscle involvement remain hallmarks of the disease, extra-muscular features should be carefully assessed.
    Keywords:  TWINKLE; Twinkle-related disorders; mitochondrial disease; myopathy
    DOI:  https://doi.org/10.3390/biom15091337
  4. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  5. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  6. J Cell Sci. 2025 Sep 15. pii: jcs263691. [Epub ahead of print]138(18):
    Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
    Mariana Joaquim, Maria-Bianca Bulimaga, Marie A Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.
    Keywords:  Apoptosis; CMT2A; Cell death; Charcot–Marie–Tooth; Fusion; MFN2; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.263691
  7. J Biol Chem. 2025 Sep 18. pii: S0021-9258(25)02591-8. [Epub ahead of print] 110739
    The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
    Wei-Hua Chu, Yu-Shan Lin, Jing Guo, Wann-Neng Jane, Wong-Jing Wang, Yu-Yang Lin, Pei-Han Liu, Po-Yu Huang, Wei-Chung Chiang.
      PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110739
  8. PLoS Biol. 2025 Sep 22. 23(9): e3003388
    Mitochondrial Complex I and ROS control neuromuscular function through opposing pre- and postsynaptic mechanisms.
    Bhagaban Mallik, Sajad A Bhat, Xinnan Wang, C Andrew Frank.
      Neurons require high amounts of energy, and mitochondria help to fulfill this requirement. Dysfunctional mitochondria trigger problems in various neuronal tasks. Using the Drosophila neuromuscular junction (NMJ) as a model synapse, we previously reported that Mitochondrial Complex I (MCI) subunits were required for maintaining NMJ function and growth. Here, we report tissue-specific adaptations at the NMJ when MCI is depleted. In Drosophila motor neurons, MCI depletion causes profound cytological defects and increased mitochondrial reactive oxygen species (ROS). But instead of diminishing synapse function, neuronal ROS triggers a homeostatic signaling process that maintains normal NMJ excitation. We identify molecules mediating this compensatory response. MCI depletion in muscles also enhances local ROS. But high levels of muscle ROS cause destructive responses: synapse degeneration, mitochondrial fragmentation, and impaired neurotransmission. In humans, mutations affecting MCI subunits cause severe neurological and neuromuscular diseases. The tissue-level effects that we describe in the Drosophila system are potentially relevant to forms of mitochondrial pathogenesis.
    DOI:  https://doi.org/10.1371/journal.pbio.3003388
  9. BMC Genomics. 2025 Sep 25. 26(1): 810
    MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.
    Haruko Nakagawa, Yasuyuki Shima, Yohei Sasagawa, Itoshi Nikaido.
       BACKGROUND: Deletion variants in mitochondrial DNA (mtDNA) are associated with various diseases, such as mitochondrial disorders and neurodegenerative diseases. Traditionally, mtDNA deletions have been studied using bulk DNA sequencing, but bulk methods average signals across cells, thereby masking the cell-type-specific mutational landscapes. Resolving mtDNA deletions at single-cell resolution is beneficial for understanding how these mutations affect distinct cell populations. To date, no specialized method exists for detecting cell-type-specific mtDNA deletions from single-cell RNA sequencing data. Notably, mtDNA possesses unique molecular features: a high copy number, stable transcription, and compact structure of the mitochondrial genome. This results in a relatively high abundance of mtDNA-derived reads even in single-cell RNA sequencing data, suggesting the possibility of detecting mtDNA deletion variants directly from transcriptomic data.
    RESULTS: Here, we present MitoDelta, a computational pipeline that enables the detection of mtDNA deletions at cell-type resolution solely from single-cell RNA sequencing data. MitoDelta combines a sensitive alignment strategy with robust statistical filtering based on a beta-binomial distribution model, allowing accurate identification of deletion events even from noisy single-cell transcriptomes. To capture cell-type-specific deletion patterns, MitoDelta analyzes reads pooled by annotated cell types, enabling quantification of deletion burden across distinct cellular populations. We benchmarked MitoDelta against existing mtDNA deletion detection tools and demonstrated superior overall performance. As a practical application, we applied MitoDelta to a published single-nucleus RNA sequencing dataset for Parkinson's disease and revealed distinct mtDNA deletion burdens across neuronal subtypes.
    CONCLUSIONS: MitoDelta enables the transcriptome-integrated, cell-type-specific detection of mtDNA deletions from single-cell RNA sequencing data alone, offering a valuable framework for reanalyzing public datasets and studying mitochondrial genome alterations at cell-type resolution. This integrated approach enables insights into how mtDNA deletions are distributed across specific cell types and cellular states, providing new opportunities to investigate the role of mtDNA deletions in cell-type-specific disease mechanisms. The tool is available at https://github.com/NikaidoLaboratory/mitodelta .
    Keywords:  Deletion variant; Mitochondrial DNA; Single-cell transcriptomics; Variant caller
    DOI:  https://doi.org/10.1186/s12864-025-11931-0
  10. J Neuroophthalmol. 2025 Sep 25.
    Genetic and Clinical Investigations of C12orf65 Gene Mutations in Three Chinese Pedigrees.
    Yiran Jia, Zhiqin Huang, Chunli Chen, Fred K Chen, Libin Jiang.
       BACKGROUND: C12orf65 (chromosome 12 open reading frame 65) gene encodes a mitochondrial matrix protein essential for the release of newly synthesized proteins from mitochondrial ribosomes. Biallelic pathogenic variants result in loss of function in the protein complex necessary for oxidative phosphorylation. Pathogenic C12orf65 variants have been associated with various inherited neurological diseases, including Behr syndrome, Leigh syndrome, combined oxidative phosphorylation deficiency 7, and hereditary spastic paraplegia.
    METHODS: This was a retrospective case series of 4 children with C12orf65 mutation from 3 unrelated pedigrees of Chinese descent. Clinical and diagnostic data were collected via retrospective medical record review. The phenotypic manifestations were systematically documented, and the genotypic data were analyzed in conjunction with previous reports.
    RESULTS: Four subjects exhibited optic nerve atrophy, strabismus, progressive lower limb dystonia, and abnormal gait. Whole exome sequencing revealed the c.394C>T variant in C12orf65 in all 4 patients. Three of the patients had coexisting novel MT-ND4 (m.11696 G>A) and OPA1 (c.1817G>A) variants.
    CONCLUSIONS: We analyzed the gene-phenotypic associations of 4 patients in conjunction with previous reports which added to the current understanding of C12orf65-related neurodegenerative disorders. The superimposed mutations in 2 of these patients suggest that the heterogeneity of optic neuropathy and the systemic features associated with C12orf65 pathogenic variants may be altered by the genetic background of mitochondrial or nuclear genes that influence mitochondrial function. We recommend genetic evaluation of C12ORF65-related diseases, including other genes responsible for optic neuropathy, and not just limited to Sanger sequencing.
    DOI:  https://doi.org/10.1097/WNO.0000000000002378
  11. Sci Signal. 2025 Sep 23. 18(905): eaec3820
    Softer nuclei for whiter brown fat.
    Wei Wong.
      Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.
    DOI:  https://doi.org/10.1126/scisignal.aec3820
  12. Annu Rev Pharmacol Toxicol. 2025 Sep 22.
    Cross-Organ Mitochondrial Communication in Stress and Disease.
    Koning Shen, Jenni Durieux, Andrew Dillin.
      Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-062124-024150
  13. Mov Disord Clin Pract. 2025 Sep 26.
    Leigh Syndrome Due to the Variant c.1019T>C in COX15.
    Josef Finsterer.
      
    Keywords:  COX15; Leigh syndrome; generalize dystonia; lactic acidosis; mitochondrial disorder
    DOI:  https://doi.org/10.1002/mdc3.70377
  14. Mov Disord Clin Pract. 2025 Sep 26.
    Reply: "Leigh Syndrome Due to the Variant c.1019T>C in COX15".
    Haya S AlFaris, Sangeetha Yoganathan, Marcus N Callister, Liali Aljouda, Vivek Pai, Pradeep Krishnan, Andrea LeBlanc Miller, Christos Ganos, Carolina Gorodetsky.
      
    Keywords:  COX15 deficiency; Leigh syndrome; dystonia; mitochondrial disorders
    DOI:  https://doi.org/10.1002/mdc3.70376
  15. Subcell Biochem. 2025 ;109 241-256
    Macromolecular Crowding in Mitochondria.
    Semen V Nesterov, Vladimir N Uversky.
      The chapter reviews the various effects of crowding on mitochondrial structure and function. Data illustrate that, as a rule, the concentration of macromolecules in the mitochondrial matrix and inner membrane is at least as high as in other parts of the cytoplasm, while the intermembrane space is sparse. The effect of crowding on mitochondrial shape, the role of disordered protein domains, and the role of changes in crowding during mitochondrial swelling are discussed. Because of the excluded volume in the matrix, real changes in ion and metabolite concentrations under swelling are substantially higher than believed, and the inner membrane is highly curved at least partly due to crowding of the matrix. The high concentration of integral proteins in the mitochondrial inner membrane leads to enrichment with non-bilayer lipid cardiolipin to compensate for their induced membrane deformations. Also crowding may be one of the stimuli for the formation of enzyme supercomplexes. All reviewed data suggest that the structure of mitochondria is adapted exactly to the conditions of high crowding, and crowding itself is one of the key factors in the regulation of mitochondrial structure and function, the role of which is significantly underestimated in the scientific literature.
    Keywords:  Enzyme supercomplexes; Intermembrane space; Intrinsically disordered proteins; Matrix; Mitochondrial function; Mitochondrial shape; Mitochondrial structure; Mitochondrial swelling
    DOI:  https://doi.org/10.1007/978-3-032-03370-3_11
  16. Crit Rev Biochem Mol Biol. 2025 Sep 26. 1-25
    Mitochondrial medicine in fatty acid oxidation disorders: insights from genetic discoveries and patient cell models.
    Rikke Katrine Jentoft Olsen.
      Mitochondrial fatty acid oxidation (mFAO) disorders are caused by genetic variants in mFAO enzymes, their electron transporters, and cofactors. The clinical spectrum is heterogeneous, ranging from multi-organ failure and early death to milder neuromuscular forms that often are triggered or exacerbated during catabolic stress. Advances in genetics and the inclusion of mFAO disorders in newborn screening programs have allowed timely diagnosis and dietary interventions to prevent tissue damage and even death. Current dietary treatment aims to prevent energy deficiency and reduce toxic metabolites, but does not significantly prevent neurological, cardiac, and skeletal muscular abnormalities, including rhabdomyolysis. This review summarizes the present knowledge obtained from human studies showing that disruption of mitochondrial bioenergetics and redox homeostasis may represent relevant mechanisms for understanding long-term tissue damage and the stress-induced disease pathology of mFAO disorders. Sources and mechanisms of reactive oxygen species (ROS) production are discussed, including knowledge gained from mutations in the Electron Transfer Flavoprotein (ETF) and ETF-Ubiquinone Oxidoreductase (ETF-QO) proteins. The ETF/ETF-QO site serves as a biophysical and biochemical linker between mFAO and OXPHOS, and its high capacity for ROS production makes it a key component of the respiratory chain and a source of ROS in mFAO disorders. Understanding mitochondrial disturbances and how secondary disturbances in mFAO cofactors integrate with redox regulation at the ETF/ETF-QO site will advance our understanding of not only mFAO disorders but also the many diseases entailing OXPHOS and mFAO deficiencies, such as neurological and cardiovascular diseases, and as such, be enlightening for mitochondrial medicine in general.
    Keywords:  Fatty acid oxidation disorder; coenzyme Q10, riboflavin, ketones, bezafibrate; mitochondria; oxidative stress; reactive oxygen species; redox signaling
    DOI:  https://doi.org/10.1080/10409238.2025.2564070
  17. Mol Ther. 2025 Sep 23. pii: S1525-0016(25)00765-8. [Epub ahead of print]
    Gene therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies.
    Caterina Garone, Silvia Sabeni, Sara Carli.
      Mitochondrial disorders are a clinically heterogeneous group of diseases due to defects in nuclear or mitochondrial DNA-encoded genes leading to mitochondrial dysfunction and oxidative phosphorylation deficiency in the affected tissues. The dual genetic controls, the biochemical heterogeneity, and the clinical variability challenge the development of effective treatment. In this review, we will focus on gene therapy and mRNA drug approaches for nuclear-encoded gene defects causing isolated, combined, or multiple oxidative phosphorylation defects and mitochondrial-encoded gene defects for which a gene replacement approach has been tested, and on the allotopic expression of mtDNA genes. An overview of the available in vitro and in vivo disease models and pre-clinical data of safety and efficacy is provided and highlights challenges in correcting the biochemical defect in the most affected tissues. Future perspectives with the use of novel gene-editing approaches or gene replacement delivery with nanoparticles are also considered as a novel strategy for treating mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.036
  18. Cell Chem Biol. 2025 Sep 25. pii: S2451-9456(25)00266-1. [Epub ahead of print]
    Sensing within: Mitochondrial inside-out signal transduction.
    Alva G Sainz, Furkan E Oflaz, Xinnan Wang.
      The prevailing theory on the origins of mitochondria proposes that they were once independent organisms. Though symbiotically integrated into eukaryotic cells, they have retained a striking degree of autonomy. This self-governance manifests as the capacity to sense internal metabolic, ionic, and redox states and transduce these into signals that modulate cellular function-a process we refer to as mitochondrial inside-out signaling. These mitochondria-initiated signaling mechanisms are crucial for bioenergetic homeostasis of all cells, including neurons. Unlike conventional outside-in signaling, these mitochondria-initiated signals stem from within the organelle and propagate outward, tuning cytosolic signaling pathways, nuclear transcriptional programs, and neuronal behavior. In this review, we provide mechanistic insights into this distinct and underappreciated signaling modality, discussing how internal mitochondrial conditions are sensed and transmitted to the cytosol and how these signaling events influence mitochondrial and cellular health with a focus on their implications for neuronal physiology and disease vulnerability.
    Keywords:  mitochondrial inside-out signaling; mitochondrial retrograde signaling; neurodegeneration; neuroscience; signal transduction
    DOI:  https://doi.org/10.1016/j.chembiol.2025.09.001
  19. Am J Hum Genet. 2025 Sep 19. pii: S0002-9297(25)00350-7. [Epub ahead of print]
    Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.
    Undiagnosed Diseases Network
      RNA sequencing has improved the diagnostic yield of individuals with rare diseases. Current analyses predominantly focus on identifying outliers in single genes that can be attributed to cis-acting variants within the gene locus. This approach overlooks causal variants with trans-acting effects on splicing transcriptome wide, such as variants impacting spliceosome function. We present a transcriptomics-first method to diagnose individuals with rare diseases by examining transcriptome-wide patterns of splicing outliers. Using splicing outlier detection methods (FRASER and FRASER2), we characterized splicing outliers from whole blood for 385 individuals from the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) and Undiagnosed Diseases Network (UDN) consortia. We examined all individuals for excess intron retention outliers in minor intron-containing genes (MIGs). Minor introns, which account for 0.5% of all introns in the human genome, are removed by small nuclear RNAs (snRNAs) in the minor spliceosome. This approach identified five individuals with excess intron retention outliers in MIGs, all of whom were found to harbor rare, bi-allelic variants in minor spliceosome snRNAs. Four individuals had rare, compound heterozygous variants in RNU4ATAC, which aided the reclassification of four variants. Additionally, one individual had rare, highly conserved, compound heterozygous variants in RNU6ATAC that may disrupt the formation of the catalytic spliceosome, suggesting it is a gene associated with Mendelian disease. These results demonstrate that examining RNA-sequencing data for transcriptome-wide signatures can increase the diagnostic yield of individuals with rare diseases, provide variant-to-function interpretation of spliceopathies, and uncover gene-disease associations.
    Keywords:  RNA sequencing; RNA-seq; RNU4ATAC; RNU6ATAC; minor spliceosome; rare disease; spliceopathy; spliceosome; splicing; transcriptome wide
    DOI:  https://doi.org/10.1016/j.ajhg.2025.08.018
  20. Biomolecules. 2025 Aug 29. pii: 1252. [Epub ahead of print]15(9):
    Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
    Davide Steffan, Camilla Pezzini, Martina Esposito, Anais Franco-Romero.
      Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.
    Keywords:  CNS; aging; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/biom15091252
  21. bioRxiv. 2025 Sep 20. pii: 2025.09.17.675534. [Epub ahead of print]
    Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.
    Maren Salla, Benedikt Obermayer, Marie Cotta, Ekaterina Friebel, Juliana Campo-Garcia, Georgia Charalambous, Roemel Jeusep Bueno, Dustin Lieu, Patryk Dabek, Ashley Helmuth, George Tellides, Roland Assi, Katrin Bankov, Marco Lodrini, Hedwig Deubzer, Dieter Beule, Hattie Chung, Helena Radbruch, David Capper, Frank Heppner, Sarah C Starossom, Caleb A Lareau, Ilon Liu, Leif S Ludwig.
      High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multi- omic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state- informed clonality in human health and disease.
    DOI:  https://doi.org/10.1101/2025.09.17.675534
  22. Cardiol Young. 2025 Sep 22. 1
    Mitochondrial cardiomyopathy: a puzzle for the final diagnosis - CORRIGENDUM.
    Andreia Duarte Constante, Susana Martins Abreu, Conceição Trigo, Susana Lemos Ferreira.
      
    DOI:  https://doi.org/10.1017/S1047951125100498
  23. Adv Sci (Weinh). 2025 Sep 24. e07759
    Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.
    Hainan Chen, Jinsi Chen, Li Huang, Xingqiang Lai, Kai Xia, Qiying Lu, Bingbing Xie, Yinong Huang, Yuan Qiu, Tao Wang, Jianqi Feng, Yuanjun Guan, Siyao Che, Jiancheng Wang, Andy Peng Xiang.
      Nestin, a well-characterized intermediate filament protein expressed in stem cells, is increasingly recognized for its non-canonical roles in diverse subcellular compartments. Here, a novel mitochondrial localization of Nestin in human mesenchymal stem cells (hMSCs) is identified, where it functions as a critical protector against mitochondrial dysfunction and cellular senescence. It is demonstrated that Nestin is imported into the mitochondrial intermembrane space via its N-terminal mitochondrial targeting sequence through Translocase of the Outer Mitochondrial Membrane 20 (TOM20)-dependent machinery. Within mitochondria, Nestin directly interacts with Mic60 to maintain cristae architecture and sustain oxidative phosphorylation. Genetic ablation of mitochondrial Nestin triggers cristae disorganization, respiratory deficiency, and premature senescence in hMSCs. Strikingly, targeted restoration of the Mic60-binding Tail3 domain of Nestin is sufficient to rescue cristae morphology, mitochondrial function, and senescence phenotypes. These findings establish a non-filamentous role for Nestin in mitochondrial quality control and propose a new therapeutic strategy for age-related disorders through modulation of mitochondrial Nestin-Mic60 interactions.
    Keywords:  Cellular senescence; Mic60; Mitochondria; Nestin; human mesenchymal stem cells (hMSCs)
    DOI:  https://doi.org/10.1002/advs.202507759
  24. bioRxiv. 2025 Sep 17. pii: 2025.09.17.676921. [Epub ahead of print]
    Purine nucleotides are competitive inhibitors of apo-GOT1.
    Narges Pourmandi, Arjun Jha, Kendall Muzzarelli, Hyunsu Lee, Zahra Assar, Gordon J Murray, Joseph H LaPointe, Thomas P Roddy, Gianna Medeiros, Shomit Sengupta, Costas A Lyssiotis.
      The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)-as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5'-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.
    DOI:  https://doi.org/10.1101/2025.09.17.676921
  25. Biosci Rep. 2025 Sep 25. 45(9): 531-546
    Human polynucleotide phosphorylase in mitochondrial RNA metabolism.
    Navid Bakshi, Madhuri Kanavalli, Karolina Z Nowak, Katarzyna J Bandyra.
      Ever since its discovery more than 70 years ago, the enzyme polynucleotide phosphorylase (PNPase) has been the subject of intensive research that has highlighted its key functional roles. The enzyme was first described in 1955 for its ability to synthesise RNA from nucleoside diphosphates. This discovery led to a Nobel Prize in Physiology or Medicine in 1959 for using PNPase to synthesise artificial RNA. However, it soon became evident that the primary function of this enzyme, conserved across diverse species, is 3'-5' RNA phosphorolysis rather than polymerisation. Remarkably, over 60 years later, it was discovered that PNPase has an even broader range of functions as it was shown to act as a conditional RNA chaperone in bacteria. In humans, PNPase (hPNPase) is located in mitochondria, where it plays a role in mitochondrial RNA (mtRNA) metabolism, thereby regulating mitochondrial function and the overall cell fitness. In this review, we present the current scope of knowledge of hPNPase, including its structure, subcellular localisation, metabolic activity, roles in mtRNA transport, processing and degradation, and its involvement in apoptosis.
    Keywords:  PNPT1; human PNPase; mitochondrial RNA metabolism
    DOI:  https://doi.org/10.1042/BSR20240504
  26. bioRxiv. 2025 Sep 18. pii: 2025.09.16.676620. [Epub ahead of print]
    Hepatic ketogenic insufficiency blunts exercise-induced energy expenditure and alters mitochondrial proteins in skeletal muscle.
    Xin C Davis, Colin S McCoin, Sebastian F Salathe, Edziu Franczak, Julie A Allen, Eric D Queathem, Kyle L Fulghum, Patrycja Puchalska, Peter A Crawford, John P Thyfault, E Matthew Morris.
      Ketone body (KB) utilization increases during fasting and exercise due to enhanced hepatic fatty acid oxidation and KB production via the rate-limiting mitochondrial enzyme hydroxymethylglutaryl-CoA synthase (HMGCS2). Since KB metabolism intersects with multiple metabolic pathways, and skeletal muscle KB catabolism rises during exercise, we tested the hypothesis that liver-specific HMGCS2 knockouts (KO) would have reduced energy expenditure (EE) and changes in the mitochondrial proteome of skeletal muscle with chronic exercise through voluntary wheel running (VWR), time-restricted feeding (TRF), or both combined to boost hepatic KB production and utilization. Control (CON) and HMGCS2 knockout (KO) mice (n=6-8 per group) underwent sedentary ad libitum feeding (SED+AL), SED+TRF, VWR+AL, and VWR+TRF for 16 weeks, with whole-body EE measured using indirect calorimetry. In CON mice, VWR increased total EE by 19.5% and non-resting EE by 50% under AL conditions, and total EE by 16% and non-resting EE by 47.9% under TRF conditions. However, the EE increases seen with VWR did not occur in KO mice. Proteomic analysis revealed that the loss of liver HMGCS2 significantly impacted proteins involved in metabolic processes within skeletal muscle, including reduced oxidative phosphorylation (OXPHOS) protein expression in SED KO mice compared to sedentary CON. Notably, VWR restored OXPHOS protein expression in the muscle of the liver HMGCS2 KO but did not alter it in the CON. Furthermore, muscle from liver HMGCS2 KO mice had elevated expression glycolytic pathways in sedentary and VWR conditions. These results indicate that hepatic ketogenic deficiency (HMGCS2 KO) diminishes exercise-induced increases in EE and uniquely impacts baseline and exercise-related adaptations in the metabolic and mitochondrial proteome of skeletal muscle.
    DOI:  https://doi.org/10.1101/2025.09.16.676620
  27. J Lipid Res. 2025 Sep 19. pii: S0022-2275(25)00169-5. [Epub ahead of print] 100907
    Mitochondria-specific photorelease of ceramide induces apoptosis.
    Christian Schröer, Matthijs Kol, Anna Koch, Emely Döffinger, Murali Annamalai, Joost C M Holthuis.
      Deciphering the mechanisms by which bioactive intermediates of lipid metabolism influence cell behavior is a challenging task. We previously demonstrated that de novo synthesized ceramides are authentic transducers of apoptosis and that their CERT-mediated diversion to mitochondria is sufficient to initiate BAX-dependent apoptosis. To further unravel the mechanism by which mitochondrial ceramides commit cells to death, we here developed a novel mitochondria-targeted and photocaged short-chain ceramide with a clickable alkyne group for derivatization with a fluorescent reporter. We show that this compound readily and selectively accumulates inside mitochondria in a biologically inert state. Subsequent photorelease of the ceramide moiety triggered apoptosis, as evidenced by proteolytic cleavage of central components of the caspase-dependent cell death pathway. Our findings reinforce the notion that ceramides can initiate apoptotic cell death by acting directly on mitochondria and establish mitochondria-targeted photocaged ceramides as novel tools to elucidate the underlying mechanism with the spatiotemporal precision of light.
    Keywords:  caspase-9; chemical synthesis; click chemistry; inner mitochondrial membrane; mitochondrial apoptosis; photocage, sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2025.100907
  28. Neurol Genet. 2025 Oct;11(5): e200291
    Deep Intronic SVA_E Insertion Identified as the Most Common Pathogenic Variant Associated With Canavan Disease: A Diagnostic Blind Spot.
    Carlos A Dominguez Gonzalez, Katrina M Bell, Ramakrishnan Rajagopalan, Michelle G de Silva, Aída Lemes, Cristina Zabala, Florencia Pérez-Vidarte, Alfredo Cerisola, Arastoo Vossough, Matthew T Whitehead, Chloe Cunningham, Natasha J Brown, Rebecca Quin, Cas Simons, Thomas Conway, Eloise Uebergang, Rocio Rius, Meutia A Kumaheri, Emma R Kotes, Ananya Vohra, Miranda P G Zalusky, Zachary B Anderson, Sophie H R Storz, Sydney A Ward, Joy Goffena, Jonas A Gustafson, Susan M White, Adeline Vanderver, Danny E Miller.
       Background and Objectives: Canavan disease (CD) is a neurodegenerative disorder in which biallelic pathogenic variants in ASPA result in spongiform degeneration of the cerebral white matter, leading to progressive and irreversible motor and cognitive decline. Despite comprehensive genetic testing, many individuals with clinical and biochemical diagnoses of CD remain without a definitive molecular diagnosis. This gap hinders access to emerging gene-targeted therapies and limits participation in clinical trials. Our objective was to understand the genetic etiology of 8 unsolved cases of CD.
    Methods: We used long-read sequencing (LRS) to investigate 8 individuals clinically and biochemically diagnosed with CD but who had negative genetic testing results. We performed targeted LRS using the Oxford Nanopore Technologies platform for 3 unrelated individuals and PacBio HiFi for an additional individual from our cohort. We performed targeted LRS on barcoded and pooled samples from the remaining affected individuals. To investigate functional impact on gene function, we performed RNA sequencing (RNA-seq) with and without cycloheximide on fibroblasts. We then evaluated the allele frequency in the population using gnomAD.
    Results: We identified an ∼2,600-bp SVA_E retrotransposon intronic insertion in ASPA in all 8 individuals. The insertion was found to be either homozygous or compound heterozygous trans with a known pathogenic variant in all individuals. RNA-seq indicated that the SVA_E insertion creates a novel splice acceptor site within intron 4 of ASPA that causes aberrant splicing and transcript degradation. Surprisingly, the frequency of this variant in population databases suggests that it is the most common pathogenic variant in ASPA and that it is present across ancestry groups.
    Discussion: Our study identified the most common pathogenic variant in ASPA, which has been overlooked in 25 years of CD research. Considering this, it is important to ensure that all testing laboratories can detect this variant through diagnostic testing and carrier screening. Our study highlights a substantial blind spot in standard short-read diagnostic pipelines, which historically have missed or overlooked these types of insertions. It also shows the power of emerging technologies, such as LRS and RNA-seq, to identify new classes of variants for genetic disorders, including CD.
    DOI:  https://doi.org/10.1212/NXG.0000000000200291
  29. Int J Mol Sci. 2025 Sep 11. pii: 8864. [Epub ahead of print]26(18):
    Effective Reduction in Nuclear DNA Contamination Allows Sensitive Mitochondrial DNA Methylation Determination by LC-MS/MS.
    Lin Liang, Luis Alfonso González Molina, Pytrick G Jellema, Martijn van Faassen, Laura T A Otten, Kevin P Mennega, Ingrid H Hof, D A Janneke Dijck-Brouwer, Amalia M Dolga, Marianne G Rots, Klary E Niezen-Koning.
      Mitochondria are essential organelles for cellular energy production, playing a central role in driving metabolic processes and supporting critical intracellular functions. Neurometabolic disorders encompass a wide variety of conditions characterized by mitochondrial dysfunction. Owing to their bacterial ancestry, mitochondria possess an independent genome consisting of a circular DNA molecule (mtDNA), which has been reported to be subject to methylation. However, the technical challenges in the detection of mtDNA methylation have led to debates on its existence. One of the concerns is that the compactness of mtDNA can lead to suboptimal bisulfite conversion, thereby causing mtDNA methylation overestimation. To address this, liquid chromatography tandem mass spectrometry (LC-MS/MS) offers a bisulfite-independent readout; however, this method requires mtDNA samples devoid of nuclear DNA (nDNA) contamination. To diminish nDNA contamination, we isolated mtDNA from the TRIzol RNA phase. Importantly, pyrosequencing showed no significant difference in the methylation levels of mtDNA isolated from the TRIzol RNA phase compared to those from the TRIzol DNA phase, or isolated via total genomic DNA (gDNA). Across different human cell lines, LC-MS/MS detected significantly lower global methylation levels for DNA isolated from the TRIzol RNA phase than those from the TRIzol DNA or gDNA isolation. Moreover, using mtDNA isolated from the TRIzol RNA phase, LC-MS/MS validated the enhanced mtDNA methylation in HepG2 transgenic cell lines expressing mitochondrial-targeted DNA methyltransferases (means of 2.89% and 2.03% for MCviPI and MSssI transgenic cell lines, respectively), compared to two negative control cell lines (1.36 and 1.39%). When applying it to clinically relevant material, LC-MS/MS demonstrated a significantly lower global methylation level for platelet DNA isolated from the TRIzol RNA phase (mean of 1.98%) compared to gDNA isolations (mean of 4.32%). Similar findings were confirmed in mouse brain tissue, in which a significantly lower methylation level was detected in DNA isolated from the TRIzol RNA phase (1.79%) compared to that from gDNA isolation (5.12%). In conclusion, isolating mtDNA from the TRIzol RNA phase holds significant potential in future studies, particularly for the quantification of mtDNA global methylation by LC-MS/MS, a technique that is independent of bisulfite conversion and bioinformatic analysis.
    Keywords:  LC-MS/MS; TRIzol RNA phase; mitochondrial DNA methylation; neurometabolic disorders; nuclear DNA
    DOI:  https://doi.org/10.3390/ijms26188864
  30. Adv Exp Med Biol. 2025 ;1481 1-28
    Molecular Cell Biology of Apoptosis in Health and Disease.
    Asma Ahmed, Stephen W G Tait.
      Apoptotic cell death is fundamental to the life of multicellular organisms, making central contributions to processes ranging from embryonic development to tissue homeostasis. Two distinct apoptosis pathways have been defined: extrinsic apoptosis and mitochondrial apoptosis. As we discuss, apoptosis is an evolutionary conserved process that is, unsurprisingly, tightly regulated. Inhibition of apoptosis can promote cancer, whereas inappropriate apoptosis has been associated with various neurodegenerative diseases. At its core, apoptosis is initiated and executed by proteases called caspases that, once activated, rapidly dismantle dying cells, ensuring that apoptosis is immunologically silent. In this chapter, we discuss the molecular mechanisms of apoptosis and its evolutionary conservation. Secondly, we highlight the emerging concept that apoptosis signalling can be engaged at non-lethal levels with diverse biological effects. Finally, we provide an overview of how apoptosis can impact health and disease, discussing ways in which apoptosis can be therapeutically targeted.
    Keywords:  BCL-2 protein family; Caspases; Cell death; Extrinsic apoptosis; MOMP; Mitochondrial apoptosis
    DOI:  https://doi.org/10.1007/978-3-031-92785-0_1
  31. Genes (Basel). 2025 Sep 11. pii: 1069. [Epub ahead of print]16(9):
    Mitochondrial Complex IV Deficiency Nuclear Type 11 Caused by a Novel Start-Lost Variant in the COX20 Gene.
    Anna Kuchina, Artem Borovikov, Olga Sidorova, Maria Orlova, Oxana Ryzhkova, Igor Zaigrin, Aysylu Murtazina.
      Background: The COX20 gene encodes a critical assembly factor for cytochrome C oxidase (complex IV), and biallelic loss-of-function variants in this gene cause mitochondrial complex IV deficiency, typically presenting in infancy or childhood with hypotonia, ataxia, neuropathy, or dystonia. Methods: This study describes an adult male patient with a broad clinical spectrum of central and peripheral nervous system involvement. Different medical genetic tests were performed for the patient, and only whole-genome trio sequencing identified pathogenic variants in the COX20 gene. A review of previously reported cases was conducted to compare clinical and imaging findings. Results: Two compound heterozygous COX20 variants in were identified: a known missense variant (c.41A>G; p.Lys14Arg) disrupting splicing, and a novel start-loss variant (c.2T>C; p.Met1?). The patient exhibited progressive ataxia, pyramidal signs, and peripheral neuropathy, accompanied by cervical spinal cord atrophy on spinal cord MRI and lower leg muscle fat infiltration on muscle MRI, an imaging feature not previously emphasized in COX20-related disease. Conclusions: A review of previously reported cases underscores broad clinical variability of the COX20-associated disorder, which may contribute to a prolonged diagnostic odyssey.
    Keywords:  COX20; ataxia; mitochondrial complex IV deficiency; neuropathy
    DOI:  https://doi.org/10.3390/genes16091069
  32. Signal Transduct Target Ther. 2025 Sep 26. 10(1): 315
    A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.
    Zhiheng Rao, Zhichao Chen, Yuxuan Bao, Zhenzhen Lu, Yuli Tang, Jiamei Zhu, Jianjia Ma, Siyang Dong, Jiawei Shi, Suhui Sheng, Yajing Chen, Jiaojiao Wang, Alan Vengai Mukondiwa, Ziyue Li, Xulan Wang, Zibo Huang, Chi Li, Wumengwei Ding, Mengjie Chen, Ziyi Han, Cong Wang, Xuebo Pan, Xiaojie Wang, Hong Zhu, Li Lin, Zhifeng Huang, Weiqin Lu, Xiaokun Li, Yongde Luo.
      The heart, an organ with a continuously high demand for energy, inherently lacks substantial reserves. The precise mechanisms that prioritize energy allocation to cardiac mitochondria, ensuring steady-state ATP production amidst high-energy organs, remain poorly understood. Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21. We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux, arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency, directly impair cardiac energetic performance. Locally, this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways, along with hindered mitochondrial biogenesis, TCA cycle, ETC flow, and OXPHOS. Consequently, the heart shifts to a hypometabolic, glycolytic, and hypoenergy state, with a reduced capacity to cope with physiological stressors such as fasting, starvation, strenuous exercise, endurance training, and cold exposure, leading to a diminished heart rate, contractility, and hemodynamic stability. Pharmacological or genetic restoration of FGF21 ameliorates these defects, reenergizing stress-exhausted hearts. This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways. Disrupting cardiac LKB1 or mTOR pathways, akin to stalling mitochondrial energy conduits, obstructs the FGF21-governed cardiac energetic potential. Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21, which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency. This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.
    DOI:  https://doi.org/10.1038/s41392-025-02402-9
  33. EMBO Mol Med. 2025 Sep 22.
    Metabolic cardiomyopathies: untangling clinical heterogeneity with human stem-cell derived models.
    Adriana S Passadouro, Berith M Balfoort, Mirjam Langeveld, Clara D M van Karnebeek, Jolanda van der Velden, Riekelt H Houtkooper, Signe Mosegaard.
      Inherited metabolic diseases are rare monogenic conditions that disrupt biochemical pathways, affecting energy production and homeostasis, often leading to damaging metabolite accumulation. These disorders are clinically heterogeneous and can impact all organs, including the heart. Metabolic cardiomyopathies present with varying severity and unpredictable prognosis, complicating patient care. Pre-clinical research aims to model these cardiomyopathies to understand their pathophysiological mechanisms and develop personalised treatments. Animal models have provided insights into cardiac pathology and treatment, but species differences limit data translation. Human induced pluripotent stem cells (hiPSC) offer a valuable tool for establishing disease models using reprogrammed somatic cells from patients and healthy donors, differentiated into disease-relevant cell types. Cardiomyocytes generated in significant numbers are crucial for investigating cardiac mechanisms and assessing patient-specific drug responses. This review summarises literature on metabolic cardiomyopathies, focusing on long-chain fatty acid oxidation disorders and Barth syndrome. We highlight cardiac readouts from various models and discuss the potential of hiPSC technologies as clinically relevant disease models.
    Keywords:  Inherited Metabolic Diseases (IMD); Metabolic Cardiomyopathy; Personalized Medicine; Pre-clinical Models
    DOI:  https://doi.org/10.1038/s44321-025-00313-4
  34. Mol Genet Genomic Med. 2025 Sep;13(9): e70139
    geneEX: An Integrated Phenotype-Driven Algorithm for Rapid Identification of Causative Variants in Monogenic Disorders.
    Junyu Zhang, Dongyun Liu, Mei Chen, Yunqian Fang, Kun Dai, Xiaoxi Zhu, Qingqing Xu, Meiling Hou, Li Wang, Jianfeng Wang, Jun Zhang, Bo Liang, Xiaoming Teng.
       BACKGROUND: In the diagnostic process of monogenic genetic disorders, identifying pathogenic variants is a crucial step. Thanks to the widespread adoption of Next-Generation Sequencing (NGS) technology, diagnostic efficiency has been significantly enhanced. However, with the increasing demand for diagnostic accuracy in clinical practice for monogenic genetic diseases, accurately and swiftly pinpointing pathogenic variants among numerous candidate variants remains a significant challenge. The complexity of data analysis and interpretation continues to limit both the efficiency and accuracy of diagnosis.
    METHODS: In this study, we have developed an innovative phenotype-driven algorithm, geneEX. This algorithm integrates large language model technology to accurately extract phenotypes from clinical information and automatically acquire Human Phenotype Ontology (HPO) information through a semantic vector representation model, thereby identifying HPO-associated genes. Additionally, it supports semantic matching between patients' free-text phenotypic descriptions and disease phenotypes, further enhancing the identification of pathogenic genes. The algorithm can rank candidate causative variants, enabling rapid and precise identification of potential pathogenic variants in rare genetic disorders.
    RESULTS: geneEX demonstrates commendable performance in ranking pathogenic variants across both virtual and clinical datasets. The supplementary matching of phenotypes in free-text form significantly enhances the precision of candidate variant prioritization for samples.
    CONCLUSION: geneEX has achieved automated HPO acquisition through its independently developed phenotype extraction and standardization methods, thereby enabling the full-process automated identification from clinical samples to pathogenic variants. Additionally, by integrating free-text phenotypic descriptions with disease phenotype matching, it enhances the accuracy of pathogenic gene identification. This innovative approach significantly improves the precision and efficiency of identifying pathogenic variants in rare genetic disorders, providing robust support for the diagnosis of monogenic diseases.
    Keywords:  phenotype‐driven; prioritization ranking; rare disease diagnosis
    DOI:  https://doi.org/10.1002/mgg3.70139
  35. J Neurol. 2025 Sep 23. 272(10): 648
    Widespread and progressive brain atrophy is a common feature in patients with mitochondrial disease.
    Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.
       BACKGROUND: Primary mitochondrial diseases comprise a group of inherited disorders that frequently affect the central nervous system. Previous studies have reported brain imaging findings commonly associated with mitochondrial disease. However, longitudinal data on volumetric brain abnormalities, their progression in time, and associations with clinical features of the disease remain limited.
    METHODS: We conducted a retrospective observational study of 36 patients with genetically confirmed mitochondrial disease at Turku University Hospital (Turku, Finland). A total of 73 brain magnetic resonance scans (1-8 per patient) were analysed using the cNeuro® image quantification tool to assess lobar and regional cortical atrophy. Associations with clinical features, including stroke-like episodes (SLEs), sex, and genetic subtype, were investigated.
    RESULTS: Cerebral atrophy was present in all patients and was most pronounced in the temporal and occipital lobes. Patients with a history of SLEs exhibited significantly greater atrophy in both temporal lobes and the right occipital and parietal lobes. Follow-up imaging (available for 15 patients) revealed progressive atrophy, particularly in the occipital lobes, in patients with SLEs. No significant differences in atrophy severity or progression were found between patients with the m.3243A > G variant and those with other genetic causes.
    CONCLUSIONS: Cerebral atrophy is a common and often progressive feature of mitochondrial disease, even in patients without clinical brain symptoms. Atrophy predominantly affects posterior brain regions, and its progression is particularly evident in patients with SLEs. These findings underline the neurodegenerative nature of mitochondrial disease and highlight the need to develop neuroprotective therapies.
    Keywords:  Cerebral atrophy; Longitudinal imaging; Magnetic resonance imaging; Mitochondrial disease; Neurodegeneration; Stroke-like episodes
    DOI:  https://doi.org/10.1007/s00415-025-13354-z
  36. Curr Biol. 2025 Sep 19. pii: S0960-9822(25)01165-0. [Epub ahead of print]
    Mitochondria transported by Kinesin-3 prevent localized calcium spiking to inhibit caspase-dependent specialized cell death.
    Rashna Sharmin, Aladin Elkhalil, Sara Pena, Pranya Gaddipati, Ginger Clark, Pavak K Shah, Mark W Pellegrino, Shai Shaham, Piya Ghose.
      Polarized cells (such as neurons) have distinct compartments with differing functions, subcellular architecture, and microenvironments. Like many cell types, they are subject to programmed elimination as a part of normal development and homeostasis. We investigated the mechanism of specialized cell elimination by studying the embryonic cell death program, compartmentalized cell elimination (CCE), in the scaffolding tail-spike epithelial cell (TSC) of C. elegans. CCE, also seen in Cephalic male (CEM) sensory neurons, is stereotyped and ordered, with distinct programs eliminating each cell compartment-the soma and two segments of the single process, the latter resembling neurite pruning. Here, we report the atypical, compartment-specific roles of two kinesins in mitochondrial transport to regulate CCE. We show that UNC-116/Kinesin-1 is required to transport mitochondria out of the TSC process and that its absence results in distal mitochondrial retention and process persistence. We describe UNC-104/Kinesin-3 in the non-canonical role of mitochondrial transport that is negatively regulated by CED-3/caspase. We identify a degenerative hub of the TSC at the junction of the cell soma and process, characterized by local CED-3/caspase activity, Ca2+ increase, and membrane severing. In the absence of CED-3/caspase, early morphological hallmarks of CCE are seen; however, UNC-104/Kinesin-3 is permitted to carry mitochondria that take up local Ca2+, leading to the reversal of CCE and cell recovery. Our study, by highlighting the involvement of region-specific Ca2+ signaling and caspase activity, the different contributions of mitochondria to cytoprotection, and the atypical roles of kinesin motors, sheds light on the molecular machinery of specialized cell elimination, with implications for cellular resilience.
    DOI:  https://doi.org/10.1016/j.cub.2025.08.065
  37. Genet Med. 2025 Sep 22. pii: S1098-3600(25)00234-5. [Epub ahead of print] 101587
    Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements.
    Hannah M German, Maha S Zaki, Muhammad A Usmani, Irem Karagoz, Stephanie Efthymiou, Mohamed S Abdel-Hamid, Haya Abdelhafez Arabiyat, Amama Ghaffar, Mohsin Shahzad, Hans van Bokhoven, Zubair M Ahmed, Omid Yaghini, Neda Hosseini, Maede Majidinezhad, Shahryar Alavi, Marjolein Bosma, Melissa H Broeks, Dilşad Türdoğan, Mohnish Suri, Laiz Laura de Godoy, Nanda M Verhoeven-Duif, Sheikh Riazuddin, Joseph G Gleeson, Cesar Alves, Judith J M Jans, Saima Riazuddin, Henry Houlden, Reza Maroofian.
       PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle (MAS), a key regulator of intracellular redox homeostasis. Recently, five patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy.
    METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency.
    RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed two severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation.
    CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of DEE, and propose novel biomarkers for diagnosis and treatment.
    Keywords:  GOT2; epilepsy; malate-aspartate shuttle; mitochondrial disorders; neurodevelopmental disorder
    DOI:  https://doi.org/10.1016/j.gim.2025.101587
  38. Nat Aging. 2025 Sep 24.
    Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
    Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.
      Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
    DOI:  https://doi.org/10.1038/s43587-025-00957-4
  39. Nature. 2025 Sep 25.
    Huntington's disease treated for first time using gene therapy.
    Elie Dolgin.
      
    Keywords:  Brain; Gene therapy; Medical research; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-025-03139-9
  40. Antioxidants (Basel). 2025 Sep 21. pii: 1138. [Epub ahead of print]14(9):
    Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.
    Mi Xiang, Mengling Yang, Lijuan Zhang, Xiaohu Ouyang, Alexey Sarapultsev, Shanshan Luo, Desheng Hu.
      Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart's reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults-mutations, oxidative lesions, copy-number shifts, or aberrant methylation-that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS-STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle-bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation-and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease.
    Keywords:  cardiovascular disease; cellular biology; mitochondrial DNA; therapeutic strategy
    DOI:  https://doi.org/10.3390/antiox14091138
  41. iScience. 2025 Sep 19. 28(9): 113425
    Bmal1 deletion alters mitochondrial microstructure and function in mouse cone photoreceptors.
    Nicolas Diaz, Sondip Biswas, Wei Zhong, Khaleel Bashir, Ting Chung Suen, Jason DeBruyne, Paul Michael Iuvone, Gianluca Tosini, Hao Duong, Sharon Francis, Kenkichi Baba.
      The mammalian retina contains an autonomous circadian system that regulates ocular physiology. The deletion of the core clock gene Bmal1 in the mouse retina disrupts retinal circuitry, alters cone spectral identity, and reduces cone viability. Cone photoreceptors have the highest energy demand among retinal neurons and are continuously exposed to high levels of oxidative stress, making them susceptible to mitochondrial dysfunction. To investigate the role of Bmal1 in mitochondrial biology, we analyzed mitochondrial function and ultrastructure in 661W cells and mouse retinas lacking Bmal1. Loss of Bmal1 impaired mitochondrial respiration, ATP production, and disrupted inner-membrane organization. Furthermore, we also identified Mic60, a key regulator of cristae structure as a direct transcriptional target of BMAL1. These findings highlight a critical role for Bmal1 in mitochondrial integrity and suggest a potential mechanism to explain the reduced cone viability observed in mice lacking Bmal1.
    Keywords:  biochemistry; cell biology; specialized functions of cells
    DOI:  https://doi.org/10.1016/j.isci.2025.113425
  42. Prenat Diagn. 2025 Sep 26.
    Fetal Anemia and Periventricular Hyperechogenicity/Halo as a Prenatal Indicator of CoQ10 Deficiency Associated With Biallelic Variant in COQ2 Gene.
    Shreyasi Sharma, Chanchal Singh, Vrunda Appannagari, Seema Thakur, Krishan Kapur, Padmavati Vetukuri.
      Coenzyme Q10 (CoQ10) is crucial for mitochondrial function, and its deficiency leads to diverse clinical manifestations. Prenatal phenotypes are rarely described, with no prior reports of fetal anemia. We present a case of a 24-year-old primigravida at 28 + 2 weeks gestation with elevated fetal middle cerebral artery peak systolic velocity indicating anemia. Neurosonography revealed bilateral periventricular hyperechogenicity/ halo. Fetal blood sampling confirmed anemia, and exome sequencing identified biallelic likely pathogenic COQ2 variants, confirming CoQ10 deficiency. This case highlights the crucial role of detailed ultrasound and neurosonography in identifying findings like fetal anemia and periventricular hyperechogenicity in the third trimester, aiding in diagnosis of rare conditions such as CoQ10 deficiency. Fetal anemia, typically linked to immunological causes, is presented here for the first time as a prenatal phenotype of CoQ10 deficiency, emphasizing the importance of considering genetic factors in non-immune settings.
    DOI:  https://doi.org/10.1002/pd.6894
  43. Sci Adv. 2025 Sep 26. 11(39): eadx2407
    A sensory and motor neuropathy caused by a genetic variant of NAMPT.
    Zhe Zhang, Jacek Pilch, Samuel Lundt, Nannan Zhang, Yongchang Chang, Tracey Singer, Dariusz Śladowski, Xiao-Ling Hu, Lijun Zheng, Woo-Ping Ge, Hua Zhang, De-Pei Li, Xianlin Han, Rafal Ploski, Shinghua Ding.
      Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway for nicotinamide adenine dinucleotide (NAD+) biosynthesis in mammalian cells and is essential for survival. Here, we report on a previously unidentified axonal sensory and motor neuropathy likely caused by a homozygous genetic variant of missense mutation (c.472G>C, p.P158A) in the NAMPT gene. Two affected siblings presented with a range of clinical features including impaired motor coordination, muscle atrophy, foot deformities, and positive Babinski sign. Using different preparations including recombinant human and mouse NAMPT proteins, patient fibroblasts, and mouse model, we showed that the p.P158A mutation decreased NAMPT enzyme activity, leading to disrupted cellular bioenergetics, metabolic derangements, and increased oxidative stress. Moreover, the p.P158A mutation could cause synaptic dysfunction and motor neuron degeneration in the mouse model. This Mutation in NAMPT Axonopathy (MINA) syndrome is the first human hereditary neurological disease linking to an NAMPT variant. Our study has substantial clinical implications.
    DOI:  https://doi.org/10.1126/sciadv.adx2407
  44. Korean J Ophthalmol. 2025 Sep 23.
    Clinical features of Leber's hereditary optic neuropathy carrying a rare m.13051G>A mtDNA mutation.
    Hyuna Kim, Hee Kyung Yang, Moon-Woo Seong, Jeong-Min Hwang.
      
    DOI:  https://doi.org/10.3341/kjo.2025.0086
  45. Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Sep 23. pii: S1388-1981(25)00099-X. [Epub ahead of print] 159691
    The B-lymphoblastoid model in Barth syndrome.
    John Z Chan, Michelle V Tomczewski, Antonia N Berdeklis, Robin E Duncan.
      Barth Syndrome (BTHS) is an ultra-rare, X-linked mitochondrial disorder caused by a variety of different mutations in the cardiolipin remodeling gene TAFAZZIN that results in cardiac and skeletal myopathy, as well as immunological deficits. Epstein-Barr virus-mediated transformation of B-lymphocytes has been used to generate B-lymphoblastoid cells that retain many of the characteristics of the initial cell line, but can be propagated extensively in culture to generate biological materials enabling study of the basic, natural function of this enzyme in cells, as well as disease-relevant effects and interventions. Notably, these model lines from individual donors are of particular value for understanding a disease with variable penetrance such as BTHS, where variation in genetic background can alter symptom severity considerably, even among closely-related individuals with the same mutation. Here, we review the generation, benefits, and limitations of the B-lymphoblastoid cell model in BTHS research, and provide an overview of recent advances in understanding the role of TAFAZZIN in mitochondrial biology from this model. Implications of these findings for understanding the pathology of BTHS, and determining future directions, are also provided, along with a review of recent advances in our understanding of the mechanism of TAFAZZIN function in cardiolipin degradation, remodeling and stability.
    Keywords:  Barth syndrome (BTHS); Cardiolipin; Electron transport chain; Lymphoblastoid; Mitochondria; Monolysocardiolipin; Reactive oxygen species; TAFAZZIN
    DOI:  https://doi.org/10.1016/j.bbalip.2025.159691
  46. Genes (Basel). 2025 Aug 23. pii: 993. [Epub ahead of print]16(9):
    First Case in Lithuania of an Autosomal Recessive Mutation in the DNAJC30 Gene as a Cause of Leber's Hereditary Optic Neuropathy.
    Liveta Sereikaite, Alvita Vilkeviciute, Brigita Glebauskiene, Rasa Traberg, Arvydas Gelzinis, Raimonda Piskiniene, Reda Zemaitiene, Rasa Ugenskiene, Rasa Liutkeviciene.
       BACKGROUND: Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and an inherited optic neuropathy. Recently, two different LHON inheritance types have been discovered: mitochondrially inherited LHON (mtLHON) and autosomal recessive LHON (arLHON). Our case report is the first diagnosed case of arLHON in a patient of Lithuanian descent and confirms the DnaJ Heat Shock Protein Family (Hsp40) Member C30 (DNAJC30) c.152A>G p.(Tyr51Cys) founder variant.
    CASE PRESENTATION: A 34-year-old Lithuanian man complained of headache and sudden, painless loss of central vision in his right eye. On examination, the visual acuity of the right and left eyes was 0.1 and 1.0, respectively. Visual-field examination revealed a central scotoma in the right eye, and visual evoked potentials (VEPs) showed prolonged latency in both eyes. Optical coherence tomography showed thickening of the retinal nerve fiber layer in the upper quadrant of the optic disk in the left eye. Magnetic resonance imaging of the head showed evidence of optic nerve inflammation in the right eye. Blood tests were within normal range and showed no signs of inflammation. Retrobulbar neuritis of the right eye was suspected, and the patient was treated with steroids, which did not improve visual acuity. He later developed visual loss in the left eye as well. A genetic origin of the optic neuropathy was suspected, and a complete mitochondrial DNA analysis was performed, but it did not reveal any pathologic mutations. Over time, the visual acuity of both eyes slowly deteriorated, and the retinal nerve fiber layer (RNFL) thinning of the optic disks progressed. A multidisciplinary team of specialists concluded that vasculitis or infectious disease was unlikely to be the cause of the vision loss, and a genetic cause for the disease was still suspected, although a first-stage genetic test did not yield the diagnosis. Thirty-three months after disease onset, whole-exome sequencing revealed a pathogenic variant in the DNAJC30 gene, leading to the diagnosis of arLHON. Treatment with Idebenone was started 35 months after the onset of the disease, resulting in no significant worsening of the patient's condition.
    CONCLUSION: This case highlights the importance of considering arLHON as a possible diagnosis for patients with optic neuropathy, because the phenotype of arLHON appears to be identical to that of mtLHON and cannot be distinguished by clinicians.
    Keywords:  (p.Tyr51Cys) in the DNAJC30; Leber’s hereditary optic neuropathy; c.152A>G; case report; mutation
    DOI:  https://doi.org/10.3390/genes16090993
  47. Cold Spring Harb Perspect Med. 2025 Sep 22. pii: a041644. [Epub ahead of print]
    Animal Models of Parkinson's Disease.
    Valina L Dawson, Ted M Dawson.
      Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially in mice, has aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of exhibiting a broad range of phenotypes and coupled with their conserved genetic and anatomical structures provides unparalleled molecular and pathological tool to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. α-Synuclein preformed fibril (PFF) injections, which induce the aggregation of endogenous α-synuclein, remarkably recapitulate pathological processes observed in human PD. Here, we provide an overview of the generation and characterization of transgenic and knockout mice and the α-synuclein PFF models used to study PD followed by molecular insights that have been gleamed these PD mouse models.
    DOI:  https://doi.org/10.1101/cshperspect.a041644
  48. Acta Physiol (Oxf). 2025 Oct;241(10): e70109
    Natural Mutation in Naked Mole-Rat UCP1 Refutes Importance of the Histidine Pair Motif for Proton Conductance and Thermogenesis.
    Michael J Gaudry, Amanda Bundgaard, Maria Kutschke, Klaudia Ostatek, Margeoux A S Dela Rosa, Paul G Crichton, Jane Reznick, Martin Jastroch.
       AIM: Uncoupling protein 1 (UCP1) is the crucial protein for non-shivering thermogenesis in placental mammals, but the molecular mechanism of thermogenic proton transport is still unknown. Its histidine pair motif (H145 and H147) has been claimed as a critical element for proton translocation, leading to the paradigmatic "cofactor model" of the UCP1 thermogenic mechanism. The histidine pair motif is mutated (H145Q) in the naked mole-rat (NMR, Heterocephalus glaber) UCP1, suggesting disrupted thermogenic function in line with NMR's poor thermoregulatory abilities. Here, we investigated the functionality NMR versus mouse UCP1 to scrutinized the importance of the histidine pair motif.
    METHODS: Respiratory analyses for UCP1 function were performed in isolated brown adipose tissue mitochondria from NMR and mouse. The histidine pair motif of NMR UCP1 was manipulated through mutations, ectopically overexpressed in HEK293 cells and subjected to plate-based respirometry for functional comparison.
    RESULTS: Isolated BAT mitochondria of NMRs display guanosine diphosphate-sensitive respiration, indicative of thermogenically competent UCP1. Overexpressed wildtype NMR UCP1 demonstrates proton leak activity comparable to mouse UCP1. Neither restoration of the histidine pair motif nor full ablation of the motif through a double mutation affects UCP1-dependent respiration.
    CONCLUSIONS: The UCP1 variant of the NMR, a warm-adapted fossorial species, excludes the histidine pair motif as crucial for UCP1 thermogenic function. Collectively, we show that functional investigation into natural sequence variation of UCP1 not only casts new light on the thermophysiology of NMRs but also represents a powerful tool to delineate structure-function relationships underlying the enigmatic thermogenic proton transport of UCP1.
    DOI:  https://doi.org/10.1111/apha.70109
  49. J Lipid Res. 2025 Sep 23. pii: S0022-2275(25)00171-3. [Epub ahead of print] 100909
    Mitochondrial cardiolipin remodeling facilitates efficient myoblast differentiation.
    Yohsuke Ohba, Chinami Fujiwara, Makoto Arita.
      During myoblast differentiation, mitochondria undergo dynamic changes in their morphology and function. Although the mitochondrial membrane lipid environment is closely related to mitochondrial integrity, how mitochondrial lipid composition changes during myoblast differentiation and whether it is involved in efficient differentiation remains unclear. In this study, we applied LC-MS/MS-based untargeted lipidomics to the mitochondria isolated from C2C12 murine myoblasts and found that the proportion of linoleic acid (C18:2)-containing cardiolipin (CL) increased during the early stages of differentiation. In parallel, the expression of tafazzin, a mitochondrial CL remodeling enzyme, increased in line with myoblast differentiation. Notably, the increase in C18:2-containing CL was not suppressed by the knockdown of MyoD, a master transcription factor for myoblast differentiation. In contrast, the inhibition of CL biosynthesis and remodeling significantly suppressed differentiation progression, which was partially rescued by exogenous supplementation with C18:2. Similar trends in CL remodeling were observed when primary stem cells isolated from mouse skeletal muscle differentiated into myotubes. These results demonstrate that mitochondrial CL remodeling at an early stage is required to promote efficient myoblast differentiation.
    Keywords:  cell signaling; lipidomics; mitochondria; muscle; phospholipid
    DOI:  https://doi.org/10.1016/j.jlr.2025.100909
  50. Mol Metab. 2025 Sep 22. pii: S2212-8778(25)00163-2. [Epub ahead of print] 102256
    Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.
    Lorenzo Da Dalt, Francesca Fantini, Giulia Giancane, Annalisa Moregola, Silvia Roda, Monika Svecla, Silvia Pedretti, Giovanni Battista Vingiani, Jiangming Sun, Andreas Edsfeldt, Isabel Goncalves, Patrizia Uboldi, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.
       AIMS: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascular cell plasticity. OPA1, a key regulator of inner mitochondrial membrane fusion, has been implicated in metabolic remodeling and cellular stress responses. We therefore investigated whether modulation of OPA1 expression affects lipid homeostasis and plaque formation in LDL receptor-deficient (LDLR KO) mice and in human carotid atherosclerosis.
    METHODS: OPA1TG/LDLR KO and OPA1ΔHep /LDLR KO were fed with a Western-type diet (WTD) for 12 weeks. The development of atherosclerosis was compared to that of LDLR KO mice. In humans, the impact of OPA1 was investigated in asymptomatic and symptomatic subjects from the Carotid Plaque Imaging Project (CPIP) biobank.
    RESULTS: OPA1TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression also resulted in an altered vascular smooth muscle cell (VSMC) cellular metabolism and differentiation, promoting a shift from a contractile/synthetic phenotype toward a more proliferative and metabolically active state. Concordantly, the deletion of OPA1 in hepatocytes improved systemic lipoprotein metabolism protecting from atherosclerosis. Concordantly in humans, plaque OPA1 mRNA levels are associated with metabolic and smooth muscle cell related pathways.
    CONCLUSION: Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism and vascular smooth muscle cell biology.
    Keywords:  Atherosclerosis; Lipoprotein; Liver; OPA1; VSMCs
    DOI:  https://doi.org/10.1016/j.molmet.2025.102256
  51. Mol Ther. 2025 Sep 23. pii: S1525-0016(25)00766-X. [Epub ahead of print]
    Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
    Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.
      Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.037
  52. Nat Commun. 2025 Sep 25. 16(1): 8392
    Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.
    Mihaly Badonyi, Joseph A Marsh.
      Molecular disease mechanisms caused by mutations in protein-coding regions are diverse, but they can be broadly categorised into loss-of-function, gain-of-function and dominant-negative effects. Accurately predicting these mechanisms is important, since therapeutic strategies can exploit these mechanisms. Computational predictors tend to perform less well at the identification of pathogenic gain-of-function and dominant-negative variants. Here, we develop a protein structure-based missense loss-of-function likelihood score that can separate recessive loss of function and dominant loss of function from alternative disease mechanisms. Using missense loss-of-function scores, we estimate the prevalence of molecular mechanisms across 2,837 phenotypes in 1,979 Mendelian disease genes, finding that dominant-negative and gain-of-function mechanisms account for 48% of phenotypes in dominant genes. Applying missense loss-of-function scores to genes with multiple phenotypes reveals widespread intragenic mechanistic heterogeneity, with 43% of dominant and 49% of mixed-inheritance genes harbouring both loss-of-function and non-loss-of-function mechanisms. Furthermore, we show that combining missense loss-of-function scores with phenotype semantic similarity enables the prioritisation of dominant-negative mechanisms in mixed-inheritance genes. Our structure-based approach, accessible via a Google Colab notebook, offers a scalable tool for predicting disease mechanisms and advancing personalised medicine.
    DOI:  https://doi.org/10.1038/s41467-025-63234-3
  53. Mol Cell. 2025 Sep 23. pii: S1097-2765(25)00737-3. [Epub ahead of print]
    Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
    Selver Altin, Tânia Simões, Christina Behrendt, Vincent Anton, Dennis Domke, Kai Mayor Völtzke, Rajesh Kumar, Hendrik Nolte, Thomas Hermanns, Nahal Brocke-Ahmadinejad, Katja Bendrin, Marcel Zimmermann, Reinhard Büttner, Natascia Ventura, Marcus Krüger, R Jürgen Dohmen, Kay Hofmann, Thorsten Hoppe, Andreas S Reichert, Mafalda Escobar-Henriques.
      Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.
    Keywords:  CxUb; E4; Ufd2; aging; mitochondria; mitofusin; mitophagy; proteostasis; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.032
  54. Neuroscience. 2025 Sep 19. pii: S0306-4522(25)00949-2. [Epub ahead of print]
    DJ-1/PARK7 in Parkinson's disease: mechanisms of pathogenesis and therapeutic potential.
    Weicong Bao, Ying Ge, Juan Huang, Yuanyuan Li, Yong Luo, Nanqu Huang.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the substantial degeneration of nigral dopaminergic neurons, the accumulation of alpha-synuclein, and the intraneuronal formation of Lewy bodies. DJ-1 is a multifaceted protein that has been linked to the pathogenesis of neurodegenerative diseases. Recent research has highlighted a potential role for DJ-1 in PD. This protein plays a critical role in maintaining mitochondrial homeostasis, modulating apoptosis, facilitating chaperone-mediated autophagy (CMA), and stabilizing dopamine levels by interacting with various signaling pathways, transcription factors, and molecular chaperones. The potential of DJ-1 as a therapeutic target for PD is apparent. In this review, we delineate the specific contributions of DJ-1 to the pathogenesis of PD. Furthermore, we discuss the therapeutic developments centered on DJ-1 in the context of neurodegeneration associated with PD.
    Keywords:  DJ-1; Mitochondria; Oxidative stress; Parkinson’s disease; Therapeutic
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.09.025
  55. Reprod Toxicol. 2025 Sep 19. pii: S0890-6238(25)00238-2. [Epub ahead of print] 109067
    NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions.
    Nazli Pinar Arslan, Zuleyha Akpinar, Havva Aybek, Meryem Doymus, Gulsum Asilkan-Kaldik, Nevzat Esim, Mesut Taskin.
      In mammalian cells, nicotinamide adenine dinucleotide (NAD+) participates in the regulation of diverse cellular processes such as ATP production, oxidative stress resistance, DNA repair, metabolic homeostasis, and inflammation. Due to these properties, exogenously applied NAD+ precursors (nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide) can protect organs and cells of mammalian against detrimental effects of various stress factors and diseases. For instance, NAD+ and its precursors have critical importance for the in vivo and in vitro fertilization success of mammals. This review summarizes that the natural aging process, diseases, and toxic compounds cause the detrimental effects in the reproductive parameters of the in vivo models, such as the meiotic defects and the reductions in cellular NAD+ level, mitochondrial functions, sperm and oocyte quality, blastocyst and embryo formation rate, implantation success, whereas the intragastric, intraperitoneal or oral administration of NAD+ precursors prevents or attenuates these detrimental effects. Similarly, the supplementation of NAD+ precursors can protect the oocytes and sperms against the cryopreservation process, aging and toxic compounds in the in vitro and also enhances blastocyst and embryo formation in vitro. This review study also revealed that the ability of NAD+ precursors-loaded drug delivery systems to prevent reproductive defects has not yet been investigated in literature. Therefore, we recommend the development of NAD+ precursor-loaded drug delivery systems targeting reproductive system organs and/or cell organelles (mitochondria, endoplasmic reticulum and nucleus). To achieve this, hormone receptors in testicular and ovarian cells can be targeted. Similarly, triphenylphosphonium (TPP+) can be used to specifically target mitochondria.
    Keywords:  NAD(+) precursors; assisted reproductive technology; drug delivery; infertility; oxidative stress; sirtuins
    DOI:  https://doi.org/10.1016/j.reprotox.2025.109067
  56. Ann Clin Transl Neurol. 2025 Sep 23.
    INF2-Related Charcot-Marie-Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights.
    Chikashi Yano, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Takahiro Hobara, Risa Nagatomo, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Chika Matsuoka, Toru Yamashita, Takashi Kimura, Ayako Miyazaki, Chinatsu Kinjo, Kenji Yokochi, Nanami Yamanaka, Nozomu Matsuda, Tomoki Suichi, Yoshiyuki Hanaoka, Haruka Kojima, Kenichi Todo, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima.
       BACKGROUND: INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
    METHODS: We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records.
    RESULTS: We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy.
    CONCLUSION: Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.
    Keywords:  Charcot‐Marie‐Tooth disease; INF2; focal segmental glomerulosclerosis; inherited peripheral neuropathies; neuropathy
    DOI:  https://doi.org/10.1002/acn3.70205
  57. Adv Sci (Weinh). 2025 Sep 26. e08991
    Acetylation of the Mitochondrial Chaperone GRP75 Governs ER-Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance.
    Danni Wang, Jiaqi Zhang, Xinyu Yang, Qiqi Zhang, Xiuya Hu, Xin Lu, Hanni Li, Xue Bai, Kai Zhang, Michael N Sack, Yongsheng Chang, Yingmei Wang, Lingdi Wang, Lu Zhu.
      Overnutrition exacerbates insulin resistance (IR) and is linked to excessive mitochondrial protein acetylation. However, the molecular mechanism by which mitochondrial protein acetylation influences hepatic IR remains incompletely elucidated. To investigate this biology, GCN5L1 liver knockout mice (LKO), which exhibit blunted mitochondrial protein acetylation are utilized. Interestingly, the hepatocytes of LKO mice exhibit impaired insulin signaling and exaggerated endoplasmic reticulum (ER) stress. To explore putative mechanisms, protein-interaction and acetyl-proteome analyses are conducted following hepatic induction of GCN5L1. The mitochondrial chaperone GRP75 interacts with GCN5L1 and is acetylated on lysine residues K567 and K612 by GCN5L1 overexpression. Furthermore, GRP75-K567/612 acetylation reduces the assemble of IP3R1-GRP75-VDAC complex, which in turn leads to the maintenance of ER calcium homeostasis and insulin sensitivity. Interestingly, during high-fat diet feeding, mitochondria-localized GCN5L1 is significantly translocated to the cytosol. This translocation attenuates the acetylation of GRP75 at K567/612 and consequently enhances ER-mitochondrial calcium flux and induces ER stress. In parallel, deacetylation-mimicking mutated GRP75-K567/612 promotes IR in vivo. Consequently, these findings demonstrate that the acetylation-dependent modification of GRP75 plays a functional role in regulating overnutrition-induced IR.
    Keywords:  acetylation; insulin resistance; liver; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/advs.202508991
  58. Int J Neonatal Screen. 2025 Sep 06. pii: 76. [Epub ahead of print]11(3):
    Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation.
    Alessandra Vasco, Clarissa Berardo, Simona Lucchi, Laura Cappelletti, Giulio Tamburello, Salvatore Fazzone, Alessia Mauri, Francesca Fiumani, Diana Postorivo, Luisella Alberti, Michela Perrone Donnorso, Serena Gasperini, Francesca Furlan, Laura Fiori, Stephana Carelli, Laura Assunta Saielli, Cristina Montrasio, Cristina Cereda.
      Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS.
    Keywords:  beta-ketothiolase deficiency; inborn errors of metabolism (IEMs); mitochondrial acetoacetyl-CoA thiolase deficiency; newborn screening (NBS); organic acidemias (OAs); organic acids; rare diseases
    DOI:  https://doi.org/10.3390/ijns11030076
  59. Nat Metab. 2025 Sep;7(9): 1765-1780
    A consensus guide to preclinical indirect calorimetry experiments.
    International Indirect Calorimetry Consensus Committee (IICCC)
      Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.
    DOI:  https://doi.org/10.1038/s42255-025-01360-4
  60. CRISPR J. 2025 Sep 24.
    Efficient Installation of Heterozygous Mutations in Human Pluripotent Stem Cells Using Prime Editing.
    Annabelle Suter, Alison Graham, Jia Yi Kuah, Jason Crisologo, Chathuni Gunatilake, Koula Sourris, Michael See, Fernando J Rossello, Mirana Ramialison, Katerina Vlahos, Sara E Howden.
      The utility of human pluripotent stem cells (hPSCs) is greatly enhanced by the ability to introduce precise, site-specific genetic modifications with minimal off-target effects. Although Cas9 endonuclease is an exceptionally efficient gene-editing tool, its propensity for generating biallelic modifications often limits its capacity for introducing heterozygous variants. Here, we use prime editing (PE) to install heterozygous edits in over 10 distinct genetic loci, achieving knock-in efficiencies of up to 40% without the need for subsequent purification or drug selection steps. Moreover, PE enables the precise introduction of heterozygous edits in paralogous genes that are otherwise extremely challenging to achieve using endonuclease-based editing approaches. We also show that PE can be successfully combined with reprogramming to derive heterozygous induced pluripotent stem cell clones directly from human fibroblasts and peripheral blood mononuclear cells. Our findings highlight the utility of PE for generating hPSCs with complex edits and represent a powerful platform for modeling disease-associated dominant mutations and gene-dosage effects in an entirely isogenic context.
    DOI:  https://doi.org/10.1177/25731599251380122
  61. Life Sci. 2025 Sep 23. pii: S0024-3205(25)00631-9. [Epub ahead of print] 123995
    Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
    Paola Zanfardino, Alessandro Amati, Stefano Doccini, Francesco Girolamo, Apollonia Tullo, Giovanna Longo, Filippo M Santorelli, Vittoria Petruzzella.
       AIMS: Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a rare autosomal recessive neuropathy caused by biallelic MTMR5/SBF1 variants, which encode a catalytically inactive myotubularin involved in phosphoinositide metabolism and autophagy regulation. This study investigates the impact of MTMR5/SBF1 dysfunction on autophagy and mitophagy in patient-derived fibroblasts and examines the relationship between protein aggregates and autophagic machinery.
    MATERIALS AND METHODS: Fibroblasts from a CMT4B3 patient with compound heterozygous MTMR5/SBF1 mutations were compared with a healthy control. Autophagic flux was analyzed via LC3B and SQSTM1; mitophagy was assessed through PINK1 and PRKN recruitment and by quantifying mitophagosomes and autolysosomes under mitochondrial stress. Protein aggregates were visualized using Proteostat and tested for colocalisation with autophagic structures.
    KEY FINDINGS: CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway.
    SIGNIFICANCE: These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity. Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects.
    Keywords:  CMT4B3; Charcot-Marie-Tooth disease; Macroautophagy; PINK1–PRKN pathway; Phosphoinositide metabolism; Proteasome
    DOI:  https://doi.org/10.1016/j.lfs.2025.123995
  62. Biomolecules. 2025 Aug 22. pii: 1209. [Epub ahead of print]15(9):
    Supercomplex Restructuring in Heart Mitochondria of COX7A1-Deficient Mice.
    Lauren Pavelich, Lucynda Pham, Paul Stemmer, Icksoo Lee, Lawrence I Grossman, Maik Hüttemann, Tasnim Arroum.
      The role of electron transport chain supercomplexes and factors that regulate their composition in a tissue- and species-specific manner are not fully understood. Tissue-specific isoforms have been reported for cytochrome c oxidase (COX), which may contribute to such regulation. Therefore, we here investigated COX activity and structural organization in wild-type (WT) and COX7A1 knockout (KO) mice, which lack the heart/skeletal muscle isoform of COX subunit VIIa. COX7A1 KO mice showed a 30% reduction in total COX activity in the heart. Although the activity of COX in the monomers and I+III2+IVn supercomplexes (SCs) remained unchanged, a marked reduction in COX dimers and unknown COX-containing species IVx and IVy contributed to the overall reduction in COX activity. Furthermore, we observed that COX7A2 substituted for COX7A1 in COX monomers, dimers, and all COX-containing SCs in the KO mice, indicating a compensatory mechanism to preserve COX functionality. Collectively, these results suggest that COX7A1 plays an important role in maintaining structural stability; however, they also suggest that loss of COX7A1 is compensated by its replacement with COX7A2.
    Keywords:  COX7aH; COX7aL; cytochrome c oxidase; heart; isoforms
    DOI:  https://doi.org/10.3390/biom15091209
  63. Biology (Basel). 2025 Aug 24. pii: 1118. [Epub ahead of print]14(9):
    Rates of Mitochondrial Metabolism of Glucose, Amino Acids, and Fatty Acids by the HEI-OC1 Inner Ear Cell Line.
    Kento Koda, Teru Kamogashira, Ken Hayashi, Chisato Fujimoto, Shinichi Iwasaki, Tatsuya Yamasoba, Kenji Kondo.
       BACKGROUND: Mitochondrial substrate switching plays an important role in aging. The substrate metabolic rate is closely related to mitochondrial activity, as mitochondria are the primary site for substrate oxidation and ATP production. Different substrates (glucose, amino acids, and fatty acids) enter the mitochondria through distinct pathways and are metabolized at different rates, depending on the energy demand and cellular conditions. However, it remains unclear how the mitochondrial metabolic rate of these substrates affects auditory cellular function. This study aimed to characterize the substrate-dependent mitochondrial respiratory responses of cochlear cells under varying energy supply conditions and metabolic stress, focusing on glucose, amino acids, and fatty acids as representative energy sources.
    METHODS: The oxygen consumption rate (OCR) was measured after substrate addition using an Agilent Seahorse XF24 Flux Analyzer In-House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, and the maximum OCR (MOCR) was determined as part of the mitochondrial stress test. Statistical analyses were performed using analysis of variance (ANOVA).
    RESULTS: The OCR increased significantly after glutamine (L-Gln) or palmitate addition. The MOCR after L-Gln addition was significantly higher than that after glutamic acid, glycine, and phenylalanine addition. The MOCR after pyruvate addition was significantly higher than that after glucose addition. However, there was no significant increase in the MOCR after fatty acid addition.
    CONCLUSIONS: Glucose is essential for basal metabolism but cannot rapidly meet sudden energy demands. Pyruvate and L-Gln serve as effective substrates for short-term, high-intensity energy demands. Fatty acids increase OCR through mitochondrial uncoupling effects, though their role may be limited in inner ear cells. These findings provide a foundation for exploring metabolic interventions to support cochlear function and hearing health.
    Keywords:  HEI-OC1; age-related hearing loss; glucose; mitochondrial metabolic rate; oxygen consumption rate
    DOI:  https://doi.org/10.3390/biology14091118
  64. NPJ Parkinsons Dis. 2025 Sep 25. 11(1): 274
    Independent serum metabolomics approaches identify disrupted glutamic acid and serine metabolism in Parkinson's disease patients.
    Jacopo Gervasoni, Carmen Marino, Alberto Imarisio, Lavinia Santucci, Enza Napolitano, Tommaso Nuzzo, Isar Yahyavi, Micol Avenali, Michela Cicchinelli, Gabriele Buongarzone, Caterina Galandra, Marta Picascia, Manuela Grimaldi, Claudio Pacchetti, Francesco Errico, Anna Maria D'Ursi, Andrea Urbani, Enza Maria Valente, Alessandro Usiello.
      Whether distinct blood metabolomic profiles can distinguish Parkinson's disease (PD) patients from healthy controls (HC) is still a matter of debate. Here, we employed ¹H-NMR and UPLC/MS analyses on serum samples from a cohort of PD patients and HC. Compared to HC, PD patients showed: (1) higher glutamine, serine, pyruvate and lower α-ketoglutarate levels (1H-NMR); (2) higher glycine and lower glutamic acid concentrations (UPLC/MS). Several pathways associated with amino acids, mitochondrial and antioxidant metabolism emerged as dysregulated in PD. Our findings highlight a prominent disruption of cellular bioenergetic pathways and amino acid homeostasis in PD.
    DOI:  https://doi.org/10.1038/s41531-025-01126-5
  65. Brain Sci. 2025 Sep 10. pii: 972. [Epub ahead of print]15(9):
    A Comprehensive Overview of Subacute Combined Degeneration: MRI Diagnostic Challenges and Treatment Pathways.
    Caterina Bernetti, Laura Cea, Andrea Buoso, Federico Greco, Mariagrazia Rossi, Fabio Pilato, Rosalinda Calandrelli, Gianfranco Di Gennaro, Vincenzo Di Lazzaro, Bruno Beomonte Zobel, Carlo Augusto Mallio.
      Subacute combined degeneration (SCD) is a neurological disorder primarily caused by vitamin B12 deficiency. This condition leads to progressive demyelination and axonal damage, predominantly affecting the dorsal and lateral columns of the spinal cord. This review provides a comprehensive overview of SCD, detailing its complex etiology, pathophysiology, and clinical presentation. We highlight the critical role of magnetic resonance imaging (MRI) in the diagnostic process, discussing both the characteristic spinal cord findings and the more subtle intracranial abnormalities. Furthermore, we address the diagnostic challenges presented by conditions that mimic SCD in MRI, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). We conclude by outlining current treatment pathways and identifying key areas for future research, including the use of advanced neuroimaging techniques and the potential for new therapeutic approaches. This updated synthesis aims to provide a clear framework for clinicians and researchers to better understand and manage SCD.
    Keywords:  axonal damage; demyelination; myelopathy; neurodegeneration; neuroimaging; neuroscience; subacute combined degeneration; vitamin B12 deficiency
    DOI:  https://doi.org/10.3390/brainsci15090972
  66. bioRxiv. 2025 Sep 16. pii: 2025.09.10.675383. [Epub ahead of print]
    Beyond Ornithine Metabolism in Gyrate Atrophy: Tissue-Specific Proteomic Insights into Neonatal and Adult OAT Deficiency.
    Artjola Puja, Rong Xu, Mark Eminhizer, Tuan Ngo, Ying Zhang, Qingyan Wang, Meghashri Saravanan, Jianhai Du.
      Ornithine aminotransferase (OAT) links the urea and TCA cycles by interconverting ornithine to pyrroline-5-carboxylate. Despite its abundance in the liver, OAT mutations primarily cause gyrate atrophy (GA) and blindness. Paradoxically, adult GA patients have hyperornithinemia that is managed by arginine-restricted diet, while neonates experience hypoornithinemia and require arginine supplementation to prevent mortality in animal models. To understand this biochemical paradox, we performed a comprehensive proteomic analysis of the liver, retina, and retinal pigment epithelium and choroid (RPE/Cho) in neonatal and adult Oat rhg mice, a whole-body OAT-deficient model. We found that the number of significantly altered proteins ranged from 5 to 254 across tissues and ages, with minimal changes in the adult retina and greatest changes in the adult RPE/Cho. OAT was the only protein consistently downregulated across all tissues. Neonatal liver proteome was more extensively altered than the adult liver proteome, primarily impacting metabolic pathways, including fatty acid oxidation, detoxification, cholesterol synthesis, and the urea cycle. In contrast, the adult liver showed changes mainly in detoxification and chromosome remodeling. Similarly, the neonatal retina was far more sensitive to OAT deficiency, with alterations not only in metabolism but also in visual transduction, ion and small molecule transport proteins. The RPE/Cho displayed the most pronounced changes in both age groups. In adults, several mitochondrial and signaling proteins were downregulated, while proteins in lipid metabolism, cytoskeleton, and extracellular matrix (ECM) were upregulated. In neonates, the alterations were enriched in chromatin organization, ECM, and vesicle transport. In summary, our findings reveal that OAT is crucial for maintaining age- and tissue-specific proteome homeostasis, with its deficiency leading to alterations in mitochondrial, metabolic processes, and signaling pathways that extend far beyond its canonical role in ornithine metabolism.
    DOI:  https://doi.org/10.1101/2025.09.10.675383
  67. J Pers Med. 2025 Sep 01. pii: 407. [Epub ahead of print]15(9):
    Artificial Intelligence in the Diagnosis of Pediatric Rare Diseases: From Real-World Data Toward a Personalized Medicine Approach.
    Nikola Ilić, Adrijan Sarajlija.
      Background: Artificial intelligence (AI) is increasingly applied in the diagnosis of pediatric rare diseases, enhancing the speed, accuracy, and accessibility of genetic interpretation. These advances support the ongoing shift toward personalized medicine in clinical genetics. Objective: This review examines current applications of AI in pediatric rare disease diagnostics, with a particular focus on real-world data integration and implications for individualized care. Methods: A narrative review was conducted covering AI tools for variant prioritization, phenotype-genotype correlations, large language models (LLMs), and ethical considerations. The literature was identified through PubMed, Scopus, and Web of Science up to July 2025, with priority given to studies published in the last seven years. Results: AI platforms provide support for genomic interpretation, particularly within structured diagnostic workflows. Tools integrating Human Phenotype Ontology (HPO)-based inputs and LLMs facilitate phenotype matching and enable reverse phenotyping. The use of real-world data enhances the applicability of AI in complex and heterogeneous clinical scenarios. However, major challenges persist, including data standardization, model interpretability, workflow integration, and algorithmic bias. Conclusions: AI has the potential to advance earlier and more personalized diagnostics for children with rare diseases. Achieving this requires multidisciplinary collaboration and careful attention to clinical, technical, and ethical considerations.
    Keywords:  artificial intelligence (AI); ethical considerations; genomic diagnostics; large language models (LLMs); pediatric rare diseases; personalized medicine; real-world data
    DOI:  https://doi.org/10.3390/jpm15090407
  68. Nat Cardiovasc Res. 2025 Sep 24.
    Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
    Sumeet A Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L Smythers, Katherine A Blackmore, Louisa Grauvogel, Melanie J Mittenbühler, Melin J Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E Houstis, Hans-Georg Sprenger, Sean J Jurgens, Kiran J Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T Ellinor, Matthias Nahrendorf, Joao A Paulo, Steven P Gygi, Phillip A Dumesic, Aarti Asnani, Krishna G Aragam, Pere Puigserver, Jason D Roh, Bruce M Spiegelman, Anthony Rosenzweig.
      Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.
    DOI:  https://doi.org/10.1038/s44161-025-00712-3
  69. Nat Struct Mol Biol. 2025 Sep 22.
    A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR.
    Taylor L Mighell, Ben Lehner.
      Reduced protein abundance is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating reduced abundance variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. To comprehensively assess PC efficacy for variation in a given protein, it is necessary to first assign the molecular mechanism explaining all pathogenic variants, then measure the response to the PC. Here we establish such a framework for the vasopressin 2 receptor (V2R), a G-protein-coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Our data show that more than half of NDI variants are poorly expressed, highlighting loss of stability as the major pathogenic mechanism. Treatment with a PC rescues the expression of 87% of destabilized variants. The non-rescued variants identify the drug's predicted binding site. Our results provide proof-of-principle that small molecule binding can rescue destabilizing variants throughout a protein's structure. The application of this principle to other proteins should allow the development of effective therapies for many different rare diseases.
    DOI:  https://doi.org/10.1038/s41594-025-01659-6
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